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  • nicotinic antagonist Finally worth of mention are few papers

    2021-10-25

    Finally, worth of mention are few papers that report on the discovery of HO-2 selective inhibitors. In 2013, starting from the screening of a nicotinic antagonist library, the above-mentioned Canadian research group identified Clemizole (Table 6) as a new hit compound for the development of the first series of HO-2 selective inhibitors, characterized by a 2-(pyrrolidin-1-yl-methyl)-1H-benzimidazole scaffold [65]. Several 2-, 3-, and 4-substituted benzyl compounds were synthesized, and SAR studies were performed to evaluate how different substituents at the N1 position of Clemizole affected HO-2 inhibitory effect. Some representative examples are reported in Table 5. It can be concluded that the best HO-2 inhibitors among 3- and 4-substituted analogs are respectively the 3-NO2 (17b) and the 4-F (17a) analogs, while all the 2-substituted analogs showed efficient inhibition against HO-2 (for example compound 17c). Further SAR studies to improve inhibitory HO-2 potency were performed using 1H-benzimidazole as central scaffold and varying substituents at the N1 and C2 positions [66]. Different substituents were evaluated to study the potency and selectivity against HO-2 relative to HO-1 (Table 7). Different rings were evaluated at the C2 position (R) including 1H-imidazol-1-yl (18a), N-morpholinyl (18b–c), cyclopentyl (18d), cyclohexyl (18e,f), or norbon-2-yl (18g) and at the N1 position (R1) a 4-substituted benzyl (Bn) moiety. Results obtained from biological evaluation showed that the presence of an imidazole ring is responsible for the loss of selectivity towards HO-1 (Table 6, compound 18a), while the best substitutions to maintain selectivity and high potency at HO-2 are the introduction of a carbocyclic ring at the C2 and a substituted benzyl moiety at the N1. Particularly, compounds presenting a cyclohexyl (18e,f) or norbon-2-yl (18g,h) functionality and Cl or Br at the 4-position of the benzyl group showed the best results in terms of HO-2 inhibition.
    Molecular modeling studies on HO inhibitors Nowadays computer-aided molecular design (CAMD) and computational chemistry are an essential aspect of drug design and have been used to follow atom-by-atom interaction and reactivity [67,68]. From hit identification to lead optimization and beyond, approaches such as structure-based, ligand-based, and virtual screening are widely used to support drug discovery efforts [[69], [70], [71], [72]]. Generally, these methods can be divided into two categories: structure-based and ligand-based drug design [73]. In the first category, using available 3D-structural and other relevant biological information concerning the target protein, the binding energy of small molecule inhibitors is calculated, and the chemical structures are modified accordingly with the target information. Often, the 3D-structural information of the target protein is not available and/or there is not a good template for homology modeling; in this case, it is more convenient to use the ligand-based method. From the dataset obtained from a series of LCs, 2D- or 3D-descriptors are calculated and QSAR equations are derived to build a pharmacophore model that is used to suggest new compounds with improved activity. In some other cases, the two different structure and ligand-based methodologies can be joined together to filter a considerable number of compounds [74]. The molecular modeling studies and the validation of the docking models conducted on the HO-1/HO-2 enzymes refer to the crystallized structures summarized in Table 8. PDB codes 1N45, 1N3U, and 1NI6 represent the human crystallized HO-1 isoforms, while 2QPP and 2RGZ codes represent the HO-2 isoform. The PDB codes 3K4F, 3CZY, 3TGM, 6EHA, 2DY5, and 3HOK, are some of the HO-1 X-ray structures complexed with representative inhibitors. The first pharmacophoric model of HO-1, reported by Salerno et al. showed that the residues Arg136, Asp140, and Gly139 are the most responsible for the hydrophilic feature of the binding pocket of the enzyme, while the residues Phe33, Met34, Phe37, Val50, Leu54, Leu147, Phe167, Phe214 are hydrophobic pocket. This model highlights the importance of the interaction of the imidazole system of the ligand with heme by π-π stacking “ferrocene-like” interactions [50].